Denne beskriver endocannabinoider(eCB) og hvordan man kan øke produksjonen av dem og reseptorene for dem. eCB er et kroppens viktigste naturlige smertstillende stoffer som kan produseres og påvirker alle nerver i kroppen. Spesielt viktig i hjernen, men også i det perifere nervesystem.

Massasje, kiropraktikk og hard trening (f.eks. runners high) utløser eCB i kroppen. Det gjør også omegabalanse (mer n-3), probiotica, NSAIDs, m.m. Også yoga, meditasjon, pust og andre stressreduserende påvirker eCB. Og trening, men kun om man gjør det jevnlig over tid.

Den nevner at langvarig stress reduserer eCB i kroppen siden det er koblet til kortisol. Men den nevner også at noen tilstander kan ha forhøyet eCB i kroppen, f.eks. overvekt.

Med høyt nivå av n-6 relativt til n-3 blir det en overvekt av AA (arakidonsyre) som produserer en overvekt av eCB, som dermed fører til en reduksjon av eCB reseptorer. Dette gjør at smertestillende medikamenter fungerer dårligere, og at det blir lettere kronisk smerte. Tilskudd av n-3 gjør at eCB reseptorene øker. Studiene er gjort på mus og innebærer 17 g/kg.

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0089566

The endocannabinoid (eCB) system consists of receptors, endogenous ligands, and ligand metabolic enzymes. Metaphorically the eCB system represents a microcosm of psychoneuroimmunology or mind-body medicine. Cannabinoid receptor 1 (CB1) is the most abundant G protein-coupled receptor expressed in the brain, with particularly dense expression in (rank order): the substantia nigra, globus pallidus, hippocampus, cerebral cortex, putamen, caudate, cerebellum, and amygdala [1]. CB1 is also expressed in non-neuronal cells, such as adipocytes and hepatocytes, and in musculoskeletal tissues. Cannabinoid receptor 2 (CB2) is principally associated with cells governing immune function, although it may also be expressed in the central nervous [2], [3].

The eCB system’s salient homeostatic roles have been summarized as, “relax, eat, sleep, forget, and protect” [5]. It modulates embryological development, neural plasticity, neuroprotection, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and most importantly from the viewpoint of recent drug development: hunger, feeding, and metabolism. Obese individuals seem to display an increased eCB tone, driving CB1activation in a chronic, feed-forward dysfunction (reviewed by [6]).

Other diseases are associated with suboptimal functioning of the eCB system. Russo [8]proposed that migraine, fibromyalgia, irritable bowel syndrome, and related conditions represent CEDS, “clinical endocannabinoid deficiency syndromes.” Fride [9] speculated that a dysfunctional eCB system in infants contributes to “failure to thrive” syndrome. Hill and Gorzalka [10] hypothesized that deficient eCB signaling could be involved in the pathogenesis of depressive illnesses. In human studies, eCB system deficiencies have been implicated in uncompensated schizophrenia [11], migraine [12], multiple sclerosis [13], Huntington’s [14],[15], uncompensated Parkinson’s [16], irritable bowel syndrome [17], uncompensated anorexia[18], and chronic motion sickness [19].

NSAIDs inhibit two cyclooxygenase (COX) enzymes, COX1 and COX2, and thereby block the conversion of arachidonic acid (AA) into inflammatory prostaglandins. Ibuprofen, ketorolac, and flurbiprofen also block the hydrolysis of AEA into arachidonic acid and ethanolamine [27]. SeeFigure 2. A binding site for some NSAIDs on FAAH has also been identified [28]. NSAID inhibition of COX2 blocks the metabolism of AEA and 2-AG into prostaglandin ethanolamides (PG-EAs) and prostaglandin glycerol esters (PG-GEs), respectively [29].

Combining NSAIDs with cannabinoids (either eCBs or exogenous cannabinoids) produces additive or synergistic effects. A sub-effective dose of WIN55,212-2 became fully antinociceptive following administration of indomethacin in rats [36].

In summary, preclinical studies indicate that some NSAIDs inhibit FAAH and enhance the activity of eCBs, phytocannabinoids, and synthetic cannabinoids. Combinational effects may be particularly relevant at peripheral sites, such as the peripheral terminals of nociceptors.

The distribution of glucocorticoid receptors (GRs) and CB1 overlap substantially in the central nervous system and other tissues, as do GRs and CB2 in immune cells. Dual activation of GRs and CBs may participate in glucocorticoid-mediated anti-inflammatory activity, immune suppression, insulin resistance, and acute psychoactive effects.

The acute administration of glucocorticoids may shift AA metabolism toward eCB synthesis in parts of the brain.

Chronic exposure to glucocorticoids downregulates the eCB system. Chronic corticosterone administration decreased CB1 densities in rat hippocampus [59] and mouse hippocampus and amygdala [61]. Chronic corticosterone administration in male rats led to visceral hyperalgesia in response to colorectal distension, accompanied by increased AEA, decreased CB1 expression, and increased TRPV1 expression in dorsal root ganglia. Co-treatment with the corticoid receptor antagonist RU-486 prevented these changes [62].

Polyunsaturated fatty acids (PUFAs) play fundamental roles in many cellular and multicellular processes, including inflammation, immunity, and neurotransmission. They must be obtained through diet, and a proper balance between omega-6 (ω-6) PUFAs and ω-3 PUFAs is essential. The typical Western diet contains a surfeit of ω-6s and a deficiency of ω-3s [130].

The inflammatory metabolites of AA are countered by dietary ω-3s. The two best-known ω-3s are eicosapentaenoic acid (EPA, 20:5ω-3) and docosahexaenoic acid (DHA, 22:6ω-3).

eCBs are derived from AA (see Figure 2). Several preclinical studies showed that dietary supplementation with AA increased serum levels of AEA and 2-AG, summarized in Table 1. Although we clearly need AA to biosynthesize eCBs, excessive levels of AA, administered chronically, may lead to excessive levels of eCBs. This in turn may lead to desensitized and downregulated CB1 and CB2 receptors.

Dietary supplementation with ω-3s predictably increased the concentration of EPA and/or DHA in tissues, cells, and plasma, and decreased the relative concentration of AA in tissues, cells, and plasma [132], [133]. ω-3 supplementation also decreased AEA and 2-AG in tissues, cells, and plasma (Table 1).

Adequate levels of dietary ω-3s are required for proper eCB signaling. Mice supplemented with ω-3s, compared to mice on a control diet, expressed greater levels of CB1 and CB2 mRNA.

n summary, dietary ω-3s seem to act as homeostatic regulators of the eCB system. In obese rodents fed a high-AA diet, ω-3s significantly decrease eCBs, especially 2-AG, particularly in tissues that become dysregulated, such as adipose and liver tissues. Plasma eCB levels are reduced by krill oil also in obese humans. Little change in eCB levels are seen in normo-weight individuals not fed a high ω-6 diet, and dietary ω-3s are required for proper eCB signaling.

Human intestinal epithelial cells incubated with L. acidophilus produced more CB2 mRNA [145]. Feeding L. acidophilus to mice and rats increased the expression of CB2 mRNA in colonic epithelial cells. Lastly, mice fed L. acidophilus showed less pain behavior following colonic distension with butyrate than control mice, an effect reversed by the CB2 antagonist AM630[145].

Chronic or repeated stress results in a chronic elevation of endogenous corticosterone via the hypothalamic-pituitary-adrenocortical (HPA) axis. Chronic stress (repeated restraint) reduced AEA levels throughout the corticolimbic stress circuit in rodents [99], [196], [197].

In summary, chronic stress impairs the eCB system, via decreased levels of AEA and 2-AG. Changes in CB1 expression are more labile. Stress management may reverse the effects of chronic stress on eCB signaling, although few studies exploring this possibility have been performed to date. Clinical anecdotes suggests that stress-reduction techniques, such as meditation, yoga, and deep breathing exercises impart mild cannabimimetic effects [218].

Massage and osteopathic manipulation of asymptomatic participants increased serum AEA 168% over pretreatment levels; mean OEA levels decreased 27%, and no changes occurred in 2-AG. Participants receiving sham manipulation showed no changes [218].

Upregulation of the eCB system in obese humans seems to be driven by excessive production of eCBs in several peripheral tissues such as visceral adipose tissue, liver, pancreas, and skeletal muscle.

In summary, increased food intake, adiposity, and elevated levels of AEA and 2-AG apparently spiral in a feed-forward mechanism. Weight loss from caloric restriction breaks the cycle, possibly by reducing CB1 expression and reducing eCB levels.

Although both types of exercise regimens increased eCB ligand concentrations, only long-term-forced exercise led to sustained elevations of eCBs, and predictable CB1 downregulation.

In whole animals, however, caffeine’s effects are biphasic and vary by dosage and acute versus chronic administration. In humans, the acute administration of caffeine decreases headache pain, but exposure to chronic high doses, ≥300 mg/day, may exacerbate chronic pain [275].